Abstract
While heparin has been used almost exclusively as a blood anticoagulant, important literature demonstrates that it also has broad anti-inflammatory activity. Herein, using low anti-coagulant 2-O,3-O-desulfated heparin (ODSH), we demonstrate that most of the anti-inflammatory pharmacology of heparin is unrelated to anticoagulant activity. ODSH has low affinity for anti-thrombin III, low anti-Xa, and anti-IIa anticoagulant activities and does not activate Hageman factor (factor XII). Unlike heparin, ODSH does not interact with heparin-platelet factor-4 antibodies present in patients with heparin-induced thrombocytopenia and even suppresses platelet activation in the presence of activating concentrations of heparin. Like heparin, ODSH inhibits complement activation, binding to the leukocyte adhesion molecule P-selectin, and the leukocyte cationic granular proteins azurocidin, human leukocyte elastase, and cathepsin G. In addition, ODSH and heparin disrupt Mac-1 (CD11b/CD18)-mediated leukocyte adhesion to the receptor for advanced glycation end products (RAGE) and inhibit ligation of RAGE by its many proinflammatory ligands, including the advanced glycation end-product carboxymethyl lysine-bovine serum albumin, the nuclear protein high mobility group box protein-1 (HMGB-1), and S100 calgranulins. In mice, ODSH is more effective than heparin in reducing selectin-mediated lung metastasis from melanoma and inhibits RAGE-mediated airway inflammation from intratracheal HMGB-1. In humans, 50% inhibitory concentrations of ODSH for these anti-inflammatory activities can be achieved in the blood without anticoagulation. These results demonstrate that the anticoagulant activity of heparin is distinct from its anti-inflammatory actions and indicate that 2-O and 3-O sulfate groups can be removed to reduce anticoagulant activity of heparin without impairing its anti-inflammatory pharmacology.
Publication types
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Clinical Trial, Phase I
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Randomized Controlled Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / administration & dosage
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Anti-Inflammatory Agents / adverse effects
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / pharmacology*
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Anticoagulants / administration & dosage
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Anticoagulants / adverse effects
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Anticoagulants / pharmacokinetics
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Anticoagulants / pharmacology*
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Antithrombin III / metabolism
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Blood Coagulation / drug effects*
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Blood Coagulation Tests
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Factor XIIa / metabolism
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Female
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Glycation End Products, Advanced / metabolism
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HMGB1 Protein / metabolism
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Heparin / administration & dosage
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Heparin / adverse effects
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Heparin / analogs & derivatives*
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Heparin / pharmacokinetics
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Heparin / pharmacology
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Humans
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Infusions, Intravenous
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Injections, Intravenous
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Injections, Subcutaneous
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Ligands
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Lung Neoplasms / blood
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Lung Neoplasms / prevention & control
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Lung Neoplasms / secondary
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Macrophage-1 Antigen / metabolism
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Male
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Melanoma, Experimental / blood
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Melanoma, Experimental / drug therapy
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Melanoma, Experimental / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Nerve Growth Factors / metabolism
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P-Selectin / metabolism
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Platelet Activation / drug effects
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Platelet Function Tests
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Pneumonia / blood
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Pneumonia / chemically induced
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Pneumonia / drug therapy*
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic / metabolism*
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Recombinant Proteins / metabolism
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S100 Calcium Binding Protein beta Subunit
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S100 Proteins / metabolism
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Thrombocytopenia / blood
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Thrombocytopenia / chemically induced
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Thrombocytopenia / prevention & control*
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U937 Cells
Substances
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Anti-Inflammatory Agents
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Anticoagulants
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Glycation End Products, Advanced
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HMGB1 Protein
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Ligands
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Macrophage-1 Antigen
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N-desulfated,2-O,3-O-desulfated heparin
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Nerve Growth Factors
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P-Selectin
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Receptor for Advanced Glycation End Products
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Receptors, Immunologic
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Recombinant Proteins
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S100 Calcium Binding Protein beta Subunit
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S100 Proteins
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Antithrombin III
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Heparin
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Factor XIIa